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Sawant, R. T., Stevens, M. Y., Sköld, C. & Odell, L. R. (2016). Microwave-Assisted Branching Cascades: A Route to Diverse 3,4-Dihydroquinazolinone-Embedded Polyheterocyclic Scaffolds. Organic Letters, 18(20), 5392-5395
Open this publication in new window or tab >>Microwave-Assisted Branching Cascades: A Route to Diverse 3,4-Dihydroquinazolinone-Embedded Polyheterocyclic Scaffolds
2016 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 18, no 20, p. 5392-5395Article in journal (Refereed) Published
Abstract [en]

A novel metal-free microwave-assisted branching cascades strategy for the efficient synthesis of 3,4-dihydro-quinazolinone-embedded polyheterocyclic scaffolds is reported. Starting from in situ generated key N-acyliminium ion precursors, 12 distinct and skeletally diverse polycyclic frameworks were accessed in a single step/pot via adjustment of the nucleophile(s) and reaction conditions. Postcascade functionalization of these compounds was also demonstrated, proving the utility of this method in accessing structurally diverse chemical entities.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-308641 (URN)10.1021/acs.orglett.6b02774 (DOI)000386187300052 ()27726402 (PubMedID)
Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2018-01-13Bibliographically approved
Stevens, M. (2016). Multicomponent Reactions in 11C/12C Chemistry: – Targeting the Angiotensin II Subtype 2 Receptor. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Multicomponent Reactions in 11C/12C Chemistry: – Targeting the Angiotensin II Subtype 2 Receptor
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Section 1 of this thesis contains an introduction to method development in organic synthesis, multicomponent reactions, sulfonyl azides, tracer development in 11C chemistry and the biological target.

Section 2 describes the use of sulfonyl azides in carbonylative chemistry. Paper I covers development of a diazotransfer protocol. In total, 30 arylsulfonyl azides were synthesised from primary sulfonamides (20–90% yield). 15N mechanistic studies were carried out and in Paper II, the products were converted into sulfonamides, sulfonylureas and sulfonyl carbamates (19–90% yield). For ureas and carbamates, a two-chamber protocol was employed to release CO from Mo(CO)6. 15N mechanistic studies showed that the sulfonamides were formed by direct displacement of azide.

Section 3 covers imaging and biological studies of the angiotensin II receptor subtype 2 (AT2R). In Paper III, 12 11C-sulfonyl carbamates were prepared in isolated radiochemical yields of 3–51% via Rh(I)-mediated carbonylation. The first non-peptide AT2R agonist, C21, was labelled (isolated RCY 24±10%, SA 34–51 GBq/µmol). C21 was tested in a prostate cancer assay, followed by biodistribution and small-animal PET studies. In Paper IV, a 11C-labelled AT2R ligand prepared via Pd(0)-mediated aminocarbonylation was used for autoradiography, biodistribution and small-animal PET studies.  

Section 4 describes the development of a multicomponent method for the synthesis of 3,4-dihydroquinazolinones (Paper V). 31 3,4-dihydroquinazolinones were synthesized via a cyclic iminium ion.  

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 93
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 219
Keywords
carbonylation, positron emission tomography, multicomponent reactions, AT2R, 3, 4-dihydroquinazolinone, sulfonyl azides
National Category
Organic Chemistry
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-295436 (URN)978-91-554-9636-4 (ISBN)
External cooperation:
Public defence
2016-09-23, Hall B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-09-02 Created: 2016-06-07 Last updated: 2016-09-05
Chow, S., Stevens, M. & Odell, L. (2016). Sulfonyl Azides as Precursors in Ligand-free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides. Journal of Organic Chemistry, 81(7), 2681-2691
Open this publication in new window or tab >>Sulfonyl Azides as Precursors in Ligand-free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides
2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 7, p. 2681-2691Article in journal (Refereed) Published
Abstract [en]

An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a palladium-catalyzed carbonylation protocol has been developed. Using a two-chamber system, sulfonyl azides, PdCl2, and CO gas, released ex situ from Mo(CO)(6), were assembled to generate sulfonyl isocyanates in situ, and alcohols and aryl amines were exploited as nucleophiles to afford a broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also developed.

National Category
Natural Sciences
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-281023 (URN)10.1021/acs.joc.5b02755 (DOI)000373520200001 ()26967791 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationCarl Tryggers foundation
Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2017-11-30Bibliographically approved
Stevens, M., Chow, C., Estrada, S., Eriksson, J., Asplund, V., Orlova, A., . . . Odell, L. (2016). Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO. ChemistryOpen, 58(3), 566-573
Open this publication in new window or tab >>Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO
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2016 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 58, no 3, p. 566-573Article in journal (Refereed) Accepted
Abstract [en]

Herein we describe the development of new methodologyfocusing on 11C-labelling of sulfonyl carbamates in a multicomponentreaction comprising a sulfonyl azide, an alkyl alcohol and [11C]CO. Anumber of 11C-labelled sulfonyl carbamates were synthesised andisolated, and the developed methodology was then applied in thepreparation of a biologically active molecule. The target compoundwas obtained in 18±8% isolated radiochemical yield and wasevaluated for binding properties in a tumor cell assay, as well asundergoing in vivo biodistribution and imaging studies. Thisrepresents the first successful radiolabelling of C21, a non-peptideangiotensin II receptor subtype 2 agonist currently in clinical trials.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-296406 (URN)
Available from: 2016-06-16 Created: 2016-06-16 Last updated: 2017-11-28
Stevens, M. Y., Chow, S. Y., Estrada, S., Eriksson, J., Asplund, V., Orlova, A., . . . Odell, L. R. (2016). Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO. ChemistryOpen, 5(6), 566-573
Open this publication in new window or tab >>Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO
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2016 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 5, no 6, p. 566-573Article in journal (Refereed) Published
Abstract [en]

We describe the development of a new methodology focusing on C-11-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [C-11] CO. A number of C-11-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24 +/- 10% isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.

Keywords
AT(2)R agonists, multicomponent reactions, radiochemistry, sulfonyl azides, sulfonyl carbamates
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-316971 (URN)10.1002/open.201600091 (DOI)000393071500012 ()28032026 (PubMedID)
Funder
Carl Tryggers foundation , CTS13:333 CTS14:356Swedish Cancer Society, 2014/474Swedish Research Council, 2015-02509
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-01-13Bibliographically approved
Sawant, R. T., Stevens, M. Y. & Odell, L. R. (2015). 3,4-Dihydro-3-(2-hydroxyethyl)-4-(nitromethyl)quinazolin-2(1H)-one. Molbank, 2015(3)
Open this publication in new window or tab >>3,4-Dihydro-3-(2-hydroxyethyl)-4-(nitromethyl)quinazolin-2(1H)-one
2015 (English)In: Molbank, ISSN 1422-8599, E-ISSN 1422-8599, Vol. 2015, no 3Article in journal (Refereed) Published
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-263475 (URN)10.3390/M866 (DOI)
Available from: 2015-09-30 Created: 2015-09-30 Last updated: 2017-12-01
Stevens, M. Y., Rozycka-Sokolowska, E., Andersson, G., Odell, L. R., Marciniak, B. & Joule, J. A. (2015). Cyclic amidines as precursors for imidazoles. ARKIVOC, 219-229
Open this publication in new window or tab >>Cyclic amidines as precursors for imidazoles
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2015 (English)In: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, p. 219-229Article in journal (Refereed) Published
Abstract [en]

The regioselective nucleophilic reactivity of cyclic amidines is considered in the context of their reactions with 2-haloketones to generate imidazoles. Since the tautomer with an endocyclic imine is favoured, reaction with the 2-haloketone electrophile proceeds via initial alkylation at the ring nitrogen. This was confirmed by repeating a suitable literature reaction and submitting the isolated product to single-crystal X-ray analysis.

Keywords
Imidazole synthesis, cyclic amidine, regioselectivity, single-crystal analysis
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-261330 (URN)10.3998/ark.5550190.p009.134 (DOI)000358993800017 ()
Available from: 2015-09-01 Created: 2015-09-01 Last updated: 2017-12-04Bibliographically approved
Sawant, R. T., Stevens, M. Y. & Odell, L. R. (2015). Rapid Access to Polyfunctionalized 3,4-Dihydroquinazolinones through a Sequential N-Acyliminium Ion Mannich Reaction Cascade. European Journal of Organic Chemistry (35), 7743-7755
Open this publication in new window or tab >>Rapid Access to Polyfunctionalized 3,4-Dihydroquinazolinones through a Sequential N-Acyliminium Ion Mannich Reaction Cascade
2015 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 35, p. 7743-7755Article in journal (Refereed) Published
Abstract [en]

A microwave-promoted one-pot, three-component sequential cyclization-Mannich reaction of unactivated ketones, o-formyl carbamates and primary amines has been developed. Cyclic N-acyliminium ions are generated in situ from the carbamate and amine starting materials. This metal-free cascade protocol provides rapid access to structurally diverse 3,4-dihydroquinazolinones in good to excellent yields with high regioselectivity for the terminal methyl group, in the case of unsymmetrical methyl alkyl ketones. Key features of the developed protocol include its operational simplicity, ease of product purification, and wide functional group tolerance.

Keywords
Multicomponent reactions, Domino reactions, Nitrogen heterocycles, Mannich bases, Regioselectivity
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-268568 (URN)10.1002/ejoc.201501178 (DOI)000366426600015 ()
Available from: 2016-02-04 Created: 2015-12-08 Last updated: 2017-11-30Bibliographically approved
Stevens, M. Y., Sawant, R. T. & Odell, L. R. (2014). Synthesis of arylsulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: Scope and N-15 NMR labeling experiments. Paper presented at 248th National Meeting of the American-Chemical-Society (ACS), AUG 10-14, 2014, San Francisco, CA. Abstract of Papers of the American Chemical Society, 248
Open this publication in new window or tab >>Synthesis of arylsulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: Scope and N-15 NMR labeling experiments
2014 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Article in journal, Meeting abstract (Other academic) Published
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-247871 (URN)000349167403500 ()
Conference
248th National Meeting of the American-Chemical-Society (ACS), AUG 10-14, 2014, San Francisco, CA
Available from: 2015-03-24 Created: 2015-03-24 Last updated: 2018-01-11Bibliographically approved
Stevens, M., Sawant, R. & Odell, L. (2014). Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and ¹⁵N NMR labeling experiments. Journal of Organic Chemistry, 79(11), 4826-4831
Open this publication in new window or tab >>Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and ¹⁵N NMR labeling experiments
2014 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 11, p. 4826-4831Article in journal (Refereed) Published
Abstract [en]

Imidazole-1-sulfonyl azide hydrogen sulfate is presented as an efficient reagent for the synthesis of sulfonyl azides from primary sulfonamides. The described method is experimentally simple and high-yielding and does not require the addition of Cu salts. Furthermore, 15N NMR mechanistic studies show the reaction proceeds via a diazo transfer mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate provides a considerable advantage over existing diazo transfer reagents in terms of impact stability, cost, and ease of use

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-232477 (URN)10.1021/jo500553q (DOI)000337073900006 ()
Available from: 2014-09-18 Created: 2014-09-18 Last updated: 2017-12-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9441-3767

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